Key Words: Ototoxicity, Nephrotoxicity or Renal toxicity, Hepatotoxicity, Hematopoietic toxicity, Bactericidal, CYP3A4 Inducer/inhibitor, Cross-react

Class

Drug Name Pen G

Antibacterial Chemotherapy Mechanism/pharmacokinetics/Resistance

Indications Gram(+) cocci

Adverse effects In general to all penicillin: -Hypersensitivity reaction is the major penicillin adverse effect. About 58% claim allergic to pens. Seizure by high dose penicillins (particularly renal failure)

Inhibitor of Cell Wall Synthesis (ICWS)

Pen G oral/parenteral, Pen V oral; Benzathine depot; acid labile Pen G: particularly for Group B Strep (GBS) Oral; nafcillin and oxacillin parenteral too; ox- clox- and diclox acidstable Anti-Staphyloccocal penicillins B-lactamase resistant!!, Staph. aureus Anti-Pseudomonal Penicillins Mechanism of Actions: 1- Covalent binding to transpeptidases/PBPs 2- Inhibit transpeptidation rxn (cross-linking of cell wall) 3- Activation of Murein hydrolases (autolysins) All are bactericidal!!!! Pen V Nafcillin, Methicillin, Isoxazolyl penicillins (ox-, clox-) Oxacillin Cloxacillin Carbenicillin indanyl, Piperacillin, Ticarcillin, Mezlocillin

B-Lactams Penicillins

All B-Lactams: Bactericidal Time dependent. PharmK: poor distribution to eye, prostate, and CNS. Effective against Proteus, Pseudomonas. Problem: rapid emergence w/Pseudomonas, so use in combo w/ aminoglycosides or fluoroquinolones. Note: these are powerful Rx, use only when indicated to protect their therapeutic value

Ampicillin, Amoxicillin,

Increased gram(-) activity

Extended Spectrum Penicillins Gram +/-

Ampicillin Rash (10% incidence, 90% in ptx w/ mononucleosis) -Same general contra as above

B-Lactamase inhibitor

Clavulanic acid, Sulbactam, Tazobactam 1st generation Cephalothin Cephalexin (o) Cefazolin

Resistance to Penicillins by B-lactamase production (major mechanism). Use B-lactamase-resistant penicillin (Nafcillin, oxacillin, cloxacillin) + Co-administer w/ B-lactamase inhibitors! Less sensitive to B-lactamase. Broader spectrum of activity. Clinical use: chemoprophylaxis for surgery, alternative to anti-staph penicillin. (ph)

B-lactamase resistant

Cephalosporins
-In general Cephalosporins are More toxic than penicillins particularly Renal Toxicity Some cross-reactivity w/ pen-sensitive pts.

Greater gramactivity Gram +

2nd gen Cefuroxime(o) Cefotetan Cefaclor (o) 3rd gen

Intermediate Spectrum F? Broad spectrum. Better for CNS

More gram- than 1st. Less Gram (+) activity Reserve for Gram-

5-10% cross-reactivity with penicillins. Hypersensitivity, some GI, Renal Toxicity; platelet inhibition and Disulfram effect. Cefotetan & cefoperazone: Disulfram effect

Cefotaxime Ceftriaxone Ceftazidime 4th gen Cefepime Mono-bactams (still b-lactams) NEWER DRUGS! Carbapenems Aztreonam

activity tax, triax, taz Broad Spectrum. Better distribution (CNS). Cephalosporinase-resistant. Gram (-) activity; virtually inactive against Gram (+) or anaerobes. Resistant to B-lactamase. No cross-reactivity in pen-sensitive patients Broad spectrum. IV only. Pseudomonas develops resistance rapidly, so use w/ aminoglycosides. Inactivated by renal dipeptidase, coadminister Cilastatin (inhibits enzyme from blocking Imipenem) Dipeptidase-resistant carbapenem. So you give this one as a second line to Imipenem Inhibits transglycosylation (step before transpeptidation). Previously classed as too toxic for systemic use. IV drug cleared through kidney enhances oto- & renal toxicity of aminoglycosides. Red man or red neck syndrome = histamine release. Misuse/overuse can be a problem. Newest ICWS. Inhibits cell-wall synthesis from within! At the cytoplasmic step in cell wall precursor synthesis. Active uptake by glycerophosphate or G6P-transporter. Only oral approved in USA. Active drug excreted by kidney. Approved for single-dose therapy of UTI. Synergistic w/ B-lactams, aminoglycosides, or fluoroquinolones. Topical antibiotic only!!!! This agent affects cell membranes. Not sure how. Old drug, now used as new drug as last resort. Mech: solubilizes bacterial membrane. Reserve for gramactivity Only good against Gram- activity, Blactam resist Gram (-/+), anaerobes May Cross-reactivity w/ penicillins. May Cross-reactivity w/ penicillins. Nephrotoxic and ototoxicity. Some thrive on this drug!!!: Vancomycindependent Enterococci

Imipenem Meropenem

Vancomycin
Other ICWS Non-B-Lactams Bactericidal Ototoxicity Renal Toxicity Fosfomycin

Bactericidal for Gram (+). Systemic MRSA Vancymycin-d

Gram (-) UTI Some Gram+ too

Other

Bacitracin Bactericidal Polymixin B Polymyxin E

Markedly nephrotoxic Inhibits GAnti-Pseudomonal

How come the class of anti-staph can be used to treat b-lactamase producing pneumococci?

Class

Drug Name

Mechanism/pharmacokinetics/Resistance

Indications Non-resistant Gram (-) infections: E. coli, Proteus, Pseudomonas For Pseudomonas: use Gent>Tobra> Amika

Adverse effects Nephrotoxicity!!!: high concentrations of AG in renal cortex. 5-25% receiving AG >3 days shows progressive renal impairment. Ampho B, or cisplatin Ototoxicity: high conc of AG in inner ear. 5-25% of ptx. Loss of vestibular and/or auditory fxn. May be reversible. Dose- and Timedependent

Inhibitor of Protein Synthesis (IPS)

Aminoglycosides
Mechanism: irreversible inactivation of ribosome (30S). Irreversible = think Bactericidal!!! Ototoxicity Streptomycin Gentamicin Tobramycin Amikacin Multiple effects on translation misreading of mRNA, interfere w/ initiation, break up polysomes (streptomycin monosomes) PharmK: poor oral absorption usually given IV, sometimes IM. Good distribution except for eye and CNS. No significant host metabolism. Excretion glomerular filtration. Very high concentration in proximal tubule cells!!!!. Administer: One Dose a Day at HIGH CONCENTRATION!!!! Once a day gives us a brief time to kill bacteria and gives us the rest of the day to relax and avoid the adverse effects: ototoxicity & Nephrotoxicity Nephrotoxicity: Exacerbated by Vancomycin, cyclosporine Neuromuscular blockade: seen at very high dose phenomenon. Most common during surgery (d/t other NM blockers), also in Myasthenia gravis ptx. Resistance: emerges rapidly if AG used alone. Related to aminoglycosides.

Renal Toxicity

Bactericidal Ototoxicity

Renal Toxicity

Neuromuscular Blockade!!!!!!
Used against Penicillin-resistant gonococci GI direct irritation. Superinfections: Pseudomonas, Proteus, Staph, Clostridia, Candida Impaired liver function high doses, during pregnancy, pre-existing liver dz Photosensitization Intracellular bugs including spirochetes. Tick-borne diseases?

Spectinomycin

Spectinomycin

Tetracycline

Usually given orally, but absorption variable. Tetracyclines chelate metal ions: Ca2+, Al3+, Fe2+, Mg2+. Poorly absorbed therefore DO NOT administer with food, milk, antacids. Rarely given IV. Well distributed, except to CNS, synovial fluid. Concentrates in teeth, bone, liver (bile), kidney. Tetracyclines crosses the placenta and are excreted in milk. Bacterial resistance to Tetracyclines by: -increased efflux pumps are major resistance. -altered ribosomal proteins or RNA are secondary mechanisms. -Especially common in Pseudomonas, proteus -indiscriminate use/overuse (clinical & agricultural) Excreted mostly fecal; others mostly urine

Broad spectrum antibiotics. Gram (+/-) Mycoplasma, Chlamydia, Rickettsiae, Lyme disease

Tetracyclines
Hepatotoxicity
Reversible binding to 30S subunit. Bacteriostatic. Doxycycline

Calcium chelation:
deposit in teeth & bone leads to discoloration, growth retardation, deformity.

Glycylcyclines (part

Newer generation of tetracyclines. Retain antibacterial spectrum

Tetracycline

of Tetracyclines) Tigecycline

of tetracyclines but overcome resistance. NOT affected by Efflux pump EXCEPT in Proteus and Pseudomonas. Bacteriostatic or bactericidal, depending on dose Absorbed from GI tract, but acid-labile. Therefore, we use enteric coating or erythromycin esters to increase stability. Can also be admin IV. Excellent distribution except to CNS. Crosses placenta. Excreted in bile (50x higher than in plasma). Half-life 2-5hrs except for azithromycin (a little longer). Resistance: Staph, some strept- and pneumococci. By altered (methylated) rRNA, efflux pump, esterases Higher availability Minimal P450-based interactions Tissue level 10-100x plasma levels!!! T1/2 = 2-4 days. Higher availability ~Active against mycobacterium avium-intracellulare (MAC) in AIDS patients Semi-synthetic macrolide. Oral, well absorbed and distributed. Metabolized in liver, excreted in both bile and urine. Poor substrate for efflux pump. ONCE daily dosing!! Used for respiratory tract infections (community-acquired pneumonia, bronchitis, sinusitis). Inhibits CYP3A4 Reversible inhibitor of protein synthesis. Bacteriostatic. Broad spectrum. Well absorbed from all routes, CNS levels = Serum. 100% excreted in urine (10%filtrate, 90% tubular sec). Glucuronidation in liver is rate-limiting step for inactivation/clearance for drug. Resistance: key mechanism is plasmid-mediated. Chloramphenicol Acyl Transferase (CAT). Slow development. Only slight resistance (2-4x). Ideal drug; however, too many adverse effects.

resistant bacteria!!

Macrolide Antibiotics
(older) Blocks translocation by binding to 50S subunit

Erythromycin, Clarithromycin, Azithromycin Clari- and Azi- (broader spectrum)

Gram (+), some Gram (-), some mycobacteria.

Think Atypical pneumonia!

Mycoplasma or Legionnaires disease, chlamydia Chlamydia

Hepatotoxicity

1. GI distress 2. Microsomal enzyme inhibition (Rx-Rx interx: oral anti-coagulants, digoxin, non-sedating antihistamines) 3. Hepatotoxicity esp. erythromycin estolate cholestatic jaundice!!!!. ~Less GI effects High intracellular concentration!!!

Macrolide Antibiotics (newer)= 50S

Clarithromycin Azithromycin

Active against (MAC) in AIDS patients

Doesnt have that efflux problem macrolides have.

Ketolides
(macrolide-like) 50S Other Protein synthesis inhibitors

Telithromycin

QT Prolongation!!

Chloramphenicol 50S

Typhoid fever, Rocky Mountain spotted fever in children.

Hematopoietic toxicity

Clindamycin

Hepatotoxicity

Lincosamide antibiotic. Bacteriostatic. Well-absorbed and distributed, except for CNS.

Bacteroides fragilis, other anaerobes.

1) GI disturbances followed by fungal superinfections. 2) Anemia d/t BM depression. 3) Aplastic Anemia usually irreversible & often fatal. 4) Gray Baby syndrome (poor glucuronidators) 5) Drug-drug interactions inhibits microsomal enzymes. GI upset, Clostridium

superinfection,

Endocarditis prophylaxis
Other Streptogramins: 50S Newer drugs! Quinupristin Dalfopristin (Synercid TM) Bactericidal Peptide macrolactones. IV, 80% excreted in bile, 20% in urine. POTENT Protein inhibitor of CYP3A4. Bacteriostatic against Enterococcus faecium. Bactericidal against other organisms. Approved for use against Vanco- and multi-drug resistant Enterococcus faecium, Methicillin-resistant Staph. Aureus (MRSA). No cross-resistance w/ other IPS. Bactericidal against streptococci. Bacteriostatic against staph and enterococci. IV or oral, Oral AUC = IV AUC Good distribution to tissues. VRE, MRSA

Hepatotoxicity
SERIOUS INDICATIONS HERE FOR DRUG-DRUG INTERACTIONS

Other Oxazolidinones Prevents formation of 70S ribosomes (unique!) Linezolid (can inhibit MAOI) Bactericidal

Primary: Vancresistant E. faecium (Limit to multi-drug resistant Gram+ infections)

BM suppression, Thrombocytopenia (reversible & mild)

Class

Drug Name p-Aminobenzoic Acid analogs (PABA)

Mechanism/pharmacokinetics/Resistance

Indications

Adverse effects

Inhibitor of Folate Dependent Pathways

Inhibitors of Folate Synthesis Sulfonamides Hematopoietic toxicity

Silver Sulfadiazine Sodium Sulfacetamide Sulfasalazine (not absorbed-split by gut bacteria to release aminosalicylate)

PABA analog. Enter into a normal metabolic pathway, but then blocks that pathway. Competitive inhibitor of dihydrofolate synthesis. Biostatic Oral, some topical (burns), rarely IV. Well absorbed in GI, well distributed including CNS. Variable metabolism, depending on drug and patient. Acetylation yields inactive metabolite. Excreted in urine (90% by glomerular filtration). 10-20x blood concentration in urine.

Topical application for burns Ophthalmic preparations Ulcerative colitis

Renal Toxicity

Allergic reaction: fever, rash (up to 5% incidence) -May cross react w/ other sulfonamides carbonic anhydrase inhibitors, thiazides, furosemide, sulfonylurea hypoglycemic.

Inhibits Pteridine synthetase

UTI uncomplicated, untreated, acute. Sulfonamides are now combined with trimethoprim. Resistance: mutations overproduction of PABA. Loss of permeability. New form of dihydropteroate synthetase enzyme can discriminate b/t PABA vs sulfonamide. Blocks bacterial enzyme. Blocks dihydrofolate reductase. Readily absorbed from GI. Wide distribution including CNS. Excreted in urine. Can be used alone for UTI, but usually combined w/ sulfonamide (TMP-SMX). Combination is often bactericidal. 10,000x more effective against bacterial DHFR than against mammalian enzyme, but still may see anti-folate effects.

Stevens-Johnson syndrome (fever, malaise, rare but can be fatal). -Crystalluria/ hematuria -Hematopoietic effects -Hemolytic anemias (G6PDH deficiency) Pneumocystis pneumonia, complicated UTI.

Inhibitor of Folate use:

Megaloblastic anemia,
leukopenia, granulocytopenia. Treat w/ folinic acid. (easy fix!) Typical sulfonamide effects. AIDS ptx receiving Cotrimoxazole = higher incidence of adverse effects. Fever, rashes, leukopenia, diarrhea

Dihydrofolate reductase (DHFR)

inhibitors

Trimethoprim

Combination

Bactrim or TrimethoprimSulfamethoxazole (Co-trimoxazole) aka TMP-SMX

Combo = bactericidal.

Class

Drug Name Nalidixic Acid

Mechanism/pharmacokinetics/Resistance

Indications Anti-malarial drugs??

Adverse effects

DNA Gyrase Inhibitor Quinolones

bactericidal Prototype quinolone antibiotic. Inhibits transcription and DNA replication. Oral admin, rapidly absorbed, rapidly metabolized (glucuronidation), and excreted in urine Fluorinated analogues of nalidixic acid. Well absorbed & distributed after oral administration. Only 20% is metabolized (liver). Excreted in urine, blocked by probenicid. Effective systemically after oral dose, parenteral forms also available. Resistance: altered (mutated) DNA gyrase, especially Pseudomonas, Staph, Serratia Broad-spectrum

Fluoroquinolones
Bactericidal!

Ciprofloxacin Levofloxacin Ofloxacin

Excellent against Gram-. Useful in GI & UTIs. Shows promise for treatment of respiratory, skin, soft tissue infections, esp. multidrug resistant organisms. Moderate-good: Gram(+)

Some GI: nausea, vomiting, diarrhea. HA, dizziness, insomnia, abnormal liver fxn tests. Blocks theophylline clearance (cannot be coadmin, duh!). Connective tissue dsd?

Class

Drug Name

Mechanism/pharmacokinetics/Resistance

Indications

Adverse effects

Urinary Tract Antiseptics

-Use systemic agents, which are efficiently cleared in the urine: Penicillins, Aminoglycosides, Sulfonamides, Fluoroquinolones. Resistance and re-infections are common. May need to suppress bacteria for a long time. Nitrofurantoin Mechanism is unknown, but may involve oxidative stress. 1) Anorexia, GI disturbances Bacteriostatic or cidal depends on bug. Rapidly absorbed (oral), common metabolized, and excreted in urine (50% as active drug). Even IV does 2) Occasional hemolytic anemia UTI, Gram+/- , not have a systemic effect. (oxidative) especially if G6PDH most effective if deficient, leukopenia, urine pH <5.5 Resistance: all Pseudomonas, some Proteus hepatotoxicity. 3) In renal insufficiency, see systemic toxicity

Class

Drug Name

Mechanism/pharmacokinetics/Resistance

Indications

Adverse effects

Anti-Mycobacterial Chemotherapy
Tuberculosis & Leprosy: Chronic infections w/long dormant periods separating intermittent active (symptomatic) periods. Mycobacteria are intracellular pathogens. Anti-TB therapy: requires prolonged constant treatment. Uncomplicated TB = 6-9 months; chemoprophylaxis is 1 year; TB meningitis or military tuberculosis is 2 years. Resistance develops rapidly to single drugs, hence combo = rule. Isoniazid (INH) Blocks synthesis of Mycolic Acids for mycobacterial cell wall. Prophylaxis used alone Hepatotoxicity (increase Bactericidal in growing cells only. for TB exposure, tuberculin with age) is more common Hepatotoxicity *acetylated in the liver. convertors. Combination in alcoholics, maybe during Genetic differences (polymorphisms) in acetylation. therapy for TB w/ pregnancy. Can be used alone 1st line AntiFast acetylators require doses Ethambutol, rifampin, or Peripheral & central mycobacterial Fast Acetylators t1/2 <1.5h pyrazinamide. neuropathy treat w/ drugs: Slow t1/2 3 hours pyridoxine (B6) Dose- & Duration- dependent. Pneumonic I Rifampin Inhibits bacterial RNA synthesis. Bactericidal. Pharmacokinetics: Combination chemo for Potent Inducer of saw red fire well absorbed and distributed, excreted in bile. active disease. microsomal enzymes. Alters (burning) liver Hepatotoxicity t1/2 of anticoagulants, oral Single agent prophylaxis contraceptives. Lots of drug-drug interactions for INH intolerant patients Hepatotoxic. flu-like or INH-resistant bug. Inducer of CYP3A4!!! Increase clearance of other drugs! syndrome. Gives orange

color to body fluids (eg pee/sweat)

Pyrazinamide Oral, absorbed, distributed. Bacteriostatic. Mechanism is unknown, but activated by mycobacterium. Rapid resistance. Dr. Zuckert: Inhibits lipid synthesis.

Hepatotoxicity

Causes Hyperuricemia (gouty arthritis). 1-5% incidence of hepatotoxicity.

Ethambutol

Streptomycin

Inhibits synthesis of mycobacterial cell wall glycan (arabinogalactan?). Well absorbed and distributed. CNS level variable, 4-60% of serum. Most excreted in urine accumulates in renal failure. Resistance: rapid, therefore use in combo Was only for severe (life-threatening) cases, now used more frequently. PK.

Dose-dependent optic neuritis, decreased acuity,

loss of red-green differentiation.

adverse effects typical of aminoglycoside IV every day for prophylaxis.. not an ideal drug choice!

2nd line Anti-TB drugs

Sulfone

Paraaminosalicylate (PAS) Cycloserine Ethionamide Dapsone

Currently a resurgence in TB, highly resistant strains are common. 2nd line may become 1st line. Other drugs include: amikacin, Ciprofloxacin, Ofloxacin

Similar to sulfonamide. Well absorbed and distributed. Concentrates in skin, muscle, liver, and kidney. Acetylated; excreted in feces and urine. Dr. Z: inhibits folic acid synthesis.

Used in combination w/ rifampin and clofazimine for M. Leprae. Also may be used for P. jiroveci pneumonia.

Hemolysis and methemoglobinemia common.

Anti-Fungal Chemotherapy
Drug Amphotericin B ampotherrible drug lots of side effects Mechanism/Phamacokinetics Binds Ergosterol (essential component of fungal membrane) A: IV or intrathecal (into CSF) D: good (except CNS) t1/2= 2 weeks (slow)-(side effects dont stop until drug is gone). Add to Liposomesdrug will have higher affinity to liposome than to OUR memblower side effects. Liposome = buffer Antimetabolite! Fungal cytosine deaminase converts 5Fluorocytosine to 5-fluorouracil (5-FU) Block DNA & RNA syn Use is limited because only some fungi are susceptible and only given independently = rapid resistance! A: Orally effective, D:widely distributed (even CNS), E:urine (10x serum) Clinical Use Adverse effect Chills, fever, nausea, vomiting, headache (premedicate: antipyretics, antihistamines, analgesics) Nephrotoxicity Low toxicity

Class: Systemic Anti-Fungal Agents

Most important drug for severe systemic mycoses Broad spectrum Use initially then switch (toxic) Concentration is greatest: Fungi > liposome > our cell membrane Cryptococcus, some Candida Rapid resistance use w/ Amphotericin B or itraconazole

Flucytosine Inhibitor of nucleic acid synthesis! Anti-cancer drug. Only fungi have cytosine deaminase!

Anti-Fungal Azoles Azoles all inhibit Ergosterol synthesis (blocks fungal CYP450)
Ketoconazole Inhibit Ergosterol synthesis A: 1st oral antifungal for systemic disease D: Not into CNS Not widely used anymore Inhibit Erogosterol synthesis A: Oral and IV Inhibit Erogosterol synthesis Water soluble good CSF delivery More selective for fungal P450s Inhibit Erogosterol synthesis. Newest triazole A: Oral and IV M: liver Cleanest/purist drug. Inhibits synthesis of cell wall b(1-3) glucan -Incomplete wall causes lysis Large cyclic peptide linked to fatty acid IV, highly protein bound, slow metabolism. Used as adjunct therapy for prostate cancer (androgen dependent) Systemic fungal disease Not used often b/c of side effects. GI, hepatotoxicity Block OUR adrenal steroidogensis (Gynecomastia) Alters drug metabolism of cyclosporine, non-sedating antihistamines Fewer adverse effects than ketoconazole

Itraconazole Fluconazole

Histoplasms, blastomyces, sporothrix Most widely used. Cryptococcal meningitis, candidemia, mucocutaneous candidiasis Aspergillosis, Candida, Dimorphic fungi

Voriconazole

Fewer adverse effects than ketoconazole Visual disturbances in 30% of patients Minor GI

Inhibitors of cell wall synthesis

Caspofungin Candida, Emperic anti-fungal (neutrophenia) Salvage therapy for amphotericinresistant Aspergillus

E: Urine, feces

Anti-fungal agents for mucocutaneous infections

Drug Topical Nystatin Mechanism/Phamacokinetics Similar to Amphotericin B Clinical Use Topical antifungal agent Can be given orally for intestinal tract Adverse effect Too toxic for systemic use. You cannot achieve systemic concentration safe enough for this drug WORST than amphotericin B!

Systemic

Griseofulvin Terbinafine

A: Orally concentrates in keratinized tissue Similar to Griseofulvin, concentrates in keratinized tissue BUT it does not ACTIVATE until it REACHES TOPICAL LOCATION! -Inhibits Squalene epoxidase (ergosterol synthesis)

ringworm & athletes foot More commonly used than

Anti-Parasitic Chemotherapy
Drug Mechanism/Phamacokinetics Clinical Use Adverse effect

Anti-Malarials
(Plasmodium falciparum, P. malariae, P. vivax, P. ovale) 1st 2 = single cycle; 2nd 2 = multiple cycles
Chloroquine Alters metabolism of hemoglobin by parasite & blocks nucleic acid synthesis A: Oral or parenteral. Rapid, complete D: wide E: urine, 25% as metabolite Give loading dose for acute tx (long t1/2) Resistance: in SA, Africa, Asia, common in P.falciparum, in P. vivax, from P-glycoprotein pumping mechanism Unknown A:oral (to irritating for parenteral) well absorbed, M: liver, excreted in feces Inhibits nucleic acid and protein synthesis. Doesnt cross BBB, metabolized by CYP3A4 and CYPs Atovaquone: Inhibits ETC, poor oral absorption, high protein binding 2-3 half life. Proguanil: inhibits protozoal dihydrofolate reductase, well absorbed, half life 12 hrs, extensive metabolism by CYP2C19, active metabolite is cycloguanil highly effective blood schizonticide Acute: clears parasitemia from all 4 plasmodia Cures: P. falciparum & p. malariae Use w/ primaquine for P. vivax & ovale Prophylactic of choice: 1 wk before travel and continue till 4 wk after Prophylaxis or tx of chloroquine resistant Back up for Chloroquine-resistant P. falciparum Prophylaxis or treatment for P. falciparum resistant. Well tolerated Pruritis; GI, mild headache; may exacerbate psoriasis or porphyria Biggest problem is resistance (efflux pump) Block efflux w/verapamil (Ca2+ channel blocker-so it has side effects) GI, CNS, possible psychotropic effects (used in murder defenses!) *Nightmares! Cinchonism (HA, nausea, sweating, tinnitus, dizziness, blurred vision) QT prolongation GI, HA, anorexia, dizziness

Mefloquine

Quinine

Atovaquone / Proguanil (Malarone)

Fansidar (pyrimethaminesulfadozine) Primaquine

Anti-folate combination Blocks synthesis/utilization of folic acid Well absorbed, excreted in urine This fights protozoans in the LIVER Oral, well absorbed, metabolites are intracellular oxidants

Use for P. Falciparum Slow acting (Not for acute attacks)

GI distress, cutaneous rxns Steven-Johnson symptoms

Artemisinin

Artesunate

Traditional Chinese medicine Activated by oxidative metabolism free radicals, alkylation Very short t1/2, oral Available through CDC only! Cannot get through pharmacy.

Tissue Schizonticide (goes after liver) Use in combination w/ chloroquine for prophylaxis or cure of P. vivax or ovale Rapidly acting blood schizonticide For multi-drug resistant P. Falciparum Used for severe P. falciparum or when oral meds cannot be given! Intestinal, extraintestinal, urogenital protozoal infections (Trichomoniasis, Giardiasis, Amebiasis) Anaerobic Infctions (C. Diff) Tx: Giardia lamblia and Cryptosporidia parvum. Useful against metronidazole-resistant strains Aerosol: used for tx & prophylaxis for Pneumocystis pneumonia

Some GI distress, hemolytic anemia in G6PDH deficiency

Other Anti-Protozoal Drugs:

Metronidazole bactericidal Tissue amebicide, Nitroimidazole (activated by electron donation), effective for anaerobic/hypoxic sites Oral or IV, well absorbed and distributed, including CNS, bone Cleared in urine (hepatic metabolism) Inhibits electron transport system pyruvate ferridoxin oxidoreductase (PFOR). Nausea, headache, dry mouth, leucopenia Disulfram effect (cant drink alcohol) Few far better tolerated than metronidazole

Nitozoxanide

Pentamidine

Unknown IV, IM or aerosol Concentrates in liver, spleen, kidneys Doesnt enter CNS

Respiratory stimulation depression; hypotension, anemia Less common w/ aerosol

Anti-Helminthic
Anti-Helminthic Chemotherapy
Mebendazole Blocks microtubule synthesis, blocks vesicle and organelle movement Given orally, <10% absorbed Wide-spectrum anti-helminthic Pinworm, hookworm, Ascaris Dose limited by GI effects Possibly embryotoxic

Albendazole

Ivermectin

Praziquantel

Rapidly metabolized, excreted in urine Interferes w/ microtubule aggregation, alters glucose uptake Rapidly and completely metabolized in liver, conjugates excreted in urine Oral treatment for all intestinal Strongyloidiasis and Onchocercasias Inhibits Cl channel and paralyzes worm and they die! Parent is active species membrane permeability to Ca2+ resulting in contraction and paralysis 80% bioavailability from oral dosing Rapidly and extensively metabolized, cleared in urine

Wide-spec anti-helminthic

Schistosomes, some trematodes and cestodes

Headache, dizziness, drowsiness

Diethylcarbamazine (DEC)

Destroys adult nematodes particularly filarial lymphatic worms that causes elephantiasis.

Drug may have severe side effects.

Pyrimethamine-Sulfonamide Class Drug Name

Mechanism/pharmacokinetics/Resistance

Indications

Adverse effects